cAMP 依赖性胰岛素分泌的非规范调节及其对 2 型糖尿病的影响

IF 4.2 2区 医学 Q1 PHYSIOLOGY
Sasanka Ramanadham, John Turk, Sushant Bhatnagar
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引用次数: 0

摘要

糖耐量受损(IGT)和肥胖导致的胰岛素抵抗引起的β细胞功能障碍会导致 2 型糖尿病(T2D)。β细胞的葡萄糖刺激胰岛素分泌(GSIS)是通过典型途径进行的,其中包括葡萄糖代谢、ATP生成、K ATP通道失活、质膜去极化和细胞膜[Ca 2+ ]c浓度增加。然而,胰岛素的最佳分泌需要通过增加环磷酸腺苷(cAMP)信号来放大 GSIS。cAMP 效应蛋白激酶 A(PKA)和环-AMP 激活的交换因子(Epac)调节膜去极化、基因表达、胰岛素颗粒向质膜的迁移和融合,从而放大 GSIS。钙2+依赖性磷脂酶A 2酶β异构体(iPLA 2 β)在β细胞内产生的脂质信号参与了cAMP刺激的胰岛素分泌(cSIS),这一点已得到广泛认可。最近的研究发现,补体 1q like-3 (C1ql3)分泌蛋白激活的 G 蛋白偶联受体(GPCR)信号在抑制 cSIS 中的作用。在 IGT 状态下,cSIS 会减弱,β 细胞功能也会降低。有趣的是,β 细胞特异性地缺失 iPLA 2 β 可减少 cAMP 介导的 GSIS 放大,而巨噬细胞(MØ)中 iPLA 2 β 的缺失则可防止与饮食诱导肥胖(DIO)相关的葡萄糖不耐受的发生。在本文中,我们讨论了经典(葡萄糖和 cAMP)和新型非经典(iPLA 2 β 和 C1ql3)途径,以及它们在肥胖和 T2D 导致的葡萄糖不耐受受损的情况下如何影响β细胞(功能障碍)。总之,我们提供了一个视角,即在 IGT 状态下,靶向非典型通路和典型通路可能是恢复 T2D β 细胞功能的一种更全面的方法。© 2023 美国生理学会。Compr Physiol 13:5023-5049, 2023.
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Noncanonical Regulation of cAMP-Dependent Insulin Secretion and Its Implications in Type 2 Diabetes.

Impaired glucose tolerance (IGT) and β-cell dysfunction in insulin resistance associated with obesity lead to type 2 diabetes (T2D). Glucose-stimulated insulin secretion (GSIS) from β-cells occurs via a canonical pathway that involves glucose metabolism, ATP generation, inactivation of K ATP channels, plasma membrane depolarization, and increases in cytosolic concentrations of [Ca 2+ ] c . However, optimal insulin secretion requires amplification of GSIS by increases in cyclic adenosine monophosphate (cAMP) signaling. The cAMP effectors protein kinase A (PKA) and exchange factor activated by cyclic-AMP (Epac) regulate membrane depolarization, gene expression, and trafficking and fusion of insulin granules to the plasma membrane for amplifying GSIS. The widely recognized lipid signaling generated within β-cells by the β-isoform of Ca 2+ -independent phospholipase A 2 enzyme (iPLA 2 β) participates in cAMP-stimulated insulin secretion (cSIS). Recent work has identified the role of a G-protein coupled receptor (GPCR) activated signaling by the complement 1q like-3 (C1ql3) secreted protein in inhibiting cSIS. In the IGT state, cSIS is attenuated, and the β-cell function is reduced. Interestingly, while β-cell-specific deletion of iPLA 2 β reduces cAMP-mediated amplification of GSIS, the loss of iPLA 2 β in macrophages (MØ) confers protection against the development of glucose intolerance associated with diet-induced obesity (DIO). In this article, we discuss canonical (glucose and cAMP) and novel noncanonical (iPLA 2 β and C1ql3) pathways and how they may affect β-cell (dys)function in the context of impaired glucose intolerance associated with obesity and T2D. In conclusion, we provide a perspective that in IGT states, targeting noncanonical pathways along with canonical pathways could be a more comprehensive approach for restoring β-cell function in T2D. © 2023 American Physiological Society. Compr Physiol 13:5023-5049, 2023.

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来源期刊
CiteScore
10.50
自引率
0.00%
发文量
38
审稿时长
6-12 weeks
期刊介绍: Comprehensive Physiology is the most authoritative and comprehensive collection of physiology information ever assembled, and uses the most powerful features of review journals and electronic reference works to cover the latest key developments in the field, through the most authoritative articles on the subjects covered. This makes Comprehensive Physiology a valued reference work on the evolving science of physiology for both researchers and clinicians. It also provides a useful teaching tool for instructors and an informative resource for medical students and other students in the life and health sciences.
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